Consumer medicine information

Zavedos

Idarubicin hydrochloride

BRAND INFORMATION

Brand name

Zavedos

Active ingredient

Idarubicin hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zavedos.

What is in this leaflet

Please read this leaflet carefully before treatment with ZAVEDOS. This leaflet answers some common questions about this medicine.

It does not contain all the available information. It does not take the place of talking to your doctor.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ZAVEDOS against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Please keep this leaflet. You may need to read it again.

What ZAVEDOS is used for

ZAVEDOS is used to treat a type of leukaemia in adults known as AML (acute myelogenous leukaemia). It works by stopping cancer cells from growing and multiplying.

ZAVEDOS may be used alone or in combination with other chemotherapy.

Ask your doctor if you have any questions about why ZAVEDOS has been prescribed for you. Your doctor may have prescribed it for another reason.

ZAVEDOS is only available with a doctor's prescription.

It is not addictive.

Before treatment with ZAVEDOS

When ZAVEDOS must not be used

Do not take ZAVEDOS if you have an allergy to:

  • any medicine containing idarubicin hydrochloride
  • other similar medicines for cancer, e.g., daunorubicin, doxorubicin, epirubicin, mitoxantrone
  • any of the ingredients listed at the end of this leaflet

Symptoms of an allergic reaction to ZAVEDOS may include:

  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take the medicine if you have:

  • severe kidney problems
  • severe liver problems
  • severe heart problems including heart failure, abnormal heart beat or a recent heart attack
  • a severe infection, with signs such as fever, severe chills, sore throat or mouth ulcers
  • reduced number of red or white blood cells or platelets
  • previously received the full course of treatment with the maximum dose of idarubicin or other similar medicines, e.g., daunorubicin, doxorubicin, epirubicin, mitozantrone/mitoxantrone.

Do not take the medicine if you are pregnant or trying to become pregnant.

Do not take the medicine if your partner is trying to become pregnant. This medicine may cause birth defects if you or your partner is taking it.

Do not take the medicine if you are breastfeeding or intend to breastfeed. Women should not breastfeed during treatment with Zavedos and for at least 14 days after the last dose. Consult your doctor or midwife if you have any concerns about being unable to breastfeed for this period.

Do not take ZAVEDOS after the expiry date printed on the pack, or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before treatment with ZAVEDOS

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have:

  • kidney disease
  • liver disease
  • heart disease
  • had previous treatment with ZAVEDOS or any other chemotherapy
  • had previous radiation therapy
  • anaemia
  • had a bone marrow transplant
  • bone marrow depression, a blood disorder with low platelet, red blood and white blood cell counts
  • infection or high temperature, severe chills, sore throat or mouth ulcers
  • stomach ulcers, or vomiting blood or bleeding from the back passage.

Talk to your doctor about an effective contraceptive method and fertility preservation before starting your treatment.

Women of childbearing potential should use effective contraception during treatment with ZAVEDOS and for at least 6.5 months after the final dose. Men with female partners of childbearing potential must use an effective contraception during treatment and for at least 3.5 months after the final dose. If planning for conception, it is advisable to seek genetic counselling.

Taking other medicines

Tell your doctor if you are taking any other medicines, including those you buy without a prescription from a pharmacy, supermarket or health food store.

Some medicines and ZAVEDOS may interfere with each other. These include:

  • other medicines for cancer
  • some medicines for heart problems, including calcium channel blockers, used to treat high blood pressure and angina
  • certain medicines that may affect your liver and kidney function, e.g. some antibiotics and antifungals
  • vaccines.

These medicines may increase some side effects of ZAVEDOS including the effects on the heart, blood cells, the stomach or bowels, and reduce the body's ability to fight infection.

If you are concerned about taking any other medications whilst having ZAVEDOS treatment, ask your doctor or pharmacist. They have more information on medicines to be careful with or avoid while taking ZAVEDOS.

Treatment with ZAVEDOS

ZAVEDOS

ZAVEDOS Solution for Injection will be prepared in a hospital and given to you by a doctor or nurse.

It is given as a slow intravenous injection, usually on 3 consecutive days. If other cancer medicines are to be given in combination with ZAVEDOS, further days of treatment may be involved. This is called an induction course.

Another course of treatment may be needed depending on your response to treatment. Additional treatment will not be repeated until your blood returns to acceptable levels and any unwanted effects have been controlled.

Inform your doctor or nurse immediately if pain, redness or swelling develops at the injection site.

If you take or are given too much (overdose)

Overdose may result in nausea, vomiting, bleeding from the stomach.

Very high doses of ZAVEDOS may cause severe damage to the heart within 24 hours and may seriously affect the production of new red and white blood cells within 1 or 2 weeks.

Overdose is unlikely, as ZAVEDOS is given in hospital under the supervision of a doctor.

If you think you may have been given too much ZAVEDOS, immediately telephone your doctor or the Poisons Information Centre (telephone 131 126) or go to Accident and Emergency at your nearest hospital if you think you or anyone else may have been treated with too much ZAVEDOS. Do this even if there are no signs of discomfort or poisoning. You will need urgent medical attention.

While you are being treated with ZAVEDOS

Things you must do

Keep all appointments with your doctor so that your progress can be checked.

ZAVEDOS lowers the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding.

Medicines such as ZAVEDOS are also known to affect the heart particularly at high doses and after a long period of treatment.

Regular tests to monitor your blood count, kidney and liver function, and your heart will be required before, during and after treatment.

Tell your doctor immediately if you or your partner becomes pregnant while you are taking or just after you stop taking ZAVEDOS. The medicine may cause birth defects if you or your partner is taking it.

You and your partner should use a proven method of birth control, such as the contraceptive pill or a condom during treatment with ZAVEDOS. Women of childbearing potential should use an effective contraception during treatment and continue using an effective contraception for at least 6.5 months after stopping treatment. Men with female partners of childbearing potential must use an effective contraception during treatment and for at least 3.5 months after the final dose.

Tell any other doctors, dentists or pharmacists who treat you that you are being treated with ZAVEDOS.

If you are about to be started on any new medicine, remind your doctor, dentist or pharmacist that you are being treated with ZAVEDOS. If you are going to have surgery, tell the surgeon, anaesthetist or dentist that you are using this medicine.

Things you must not do

Do not stop taking ZAVEDOS, or change the dose, unless your doctor tells you to.

Do not start to take any other medicine before talking to your doctor or pharmacist.

Do not use this medicine to treat any other conditions unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not breastfeed during treatment for at least 14 days after last dose.

Things to be careful of

Special care should be taken if it is necessary that you drive or operate machinery while undergoing treatment with ZAVEDOS, especially if you are in a weakened condition.

Take the following precautions to reduce your risk of infection or bleeding:

  • Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate
  • Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters
  • Avoid contact sports or other situations where you may bruise or get injured.

Side effects

Tell your doctor as soon as possible if you do not feel well during or after treatment with ZAVEDOS.

All medicines can have side effects. This medicine may have unwanted side effects in a few people. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects. Most of the side effects listed below are reversible.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following:

  • red coloured urine for 1-2 days after treatment (this is normal and is no cause for alarm)
  • nausea and vomiting, diarrhoea, loss of appetite
  • stomach pain and discomfort
  • mouth ulcers, redness and irritation of the throat and mouth with difficulty in swallowing and eating.
  • skin changes such as darker areas of the skin and nails
  • loss of hair
  • hot flushes

The above list includes the milder side effects of your medicine.

Tell your doctor immediately if you notice any of the following:

  • allergic reaction (swelling of the face, lips and tongue or other parts of the body, shortness of breath, wheezing or trouble breathing)
  • skin rash, itching. redness of the skin or hives
  • signs of infection such as fever, chills, cough or mouth ulcers
  • signs of anaemia such as headaches, shortness of breath when exercising, dizziness, looking pale
  • bleeding or bruising more easily than normal
  • shock due to a dangerous drop in blood pressure which may lead to collapse and coma - signs include rapid, shallow breathing, cold, clammy skin, a rapid, weak pulse, dizziness, weakness and fainting
  • signs of sepsis or blood poisoning such as high fever, chills, headache, confusion, rapid breathing
  • chest pain, abnormal heartbeat, fast heartbeat
  • shortness of breath, swelling in the feet or legs due to fluid build-up
  • vomiting blood or bleeding from the back passage, black sticky bowel motions (stools) or bloody diarrhoea
  • swelling and redness along a vein which is extremely tender when touched, clotting in a vein if you are being treated with ZAVEDOS Solution for Injection.

The above list includes serious side effects that may require urgent medical attention.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some of these side effects (for example, an increase in liver enzyme levels, high blood levels of uric acid) can only be found when your doctor does tests from time to time to check your progress.

After using ZAVEDOS

Storage

Solution for Injection
ZAVEDOS Solution for Injection is normally stored in a hospital.

It is stored in the refrigerator between 2 to 8°C (Refrigerate. Do not freeze.). Protect from light.

Disposal

Any remaining ZAVEDOS Solution for Injection will be disposed by the nurse or doctor at the hospital.

Product description

What it looks like

ZAVEDOS Solution for Injection is available in two different sizes: 5 mg/ 5 mL and 10 mg/10 mL It is a red-orange coloured solution contained in a plastic or a glass vial.

Ingredients

ZAVEDOS Solution for Injection contain idarubicin hydrochloride as the active ingredient.

It also contains glycerol, hydrochloric acid and water as inactive ingredients.

Supplier

Pfizer Australia Pty Ltd
SYDNEY, NSW.
Toll free number: 1800 675 229.

Australian Registration numbers

5 mg/5 mL Solution for Injection, AUST R 67397.

10 mg/10 mL Solution for Injection, AUST R 67398.

This leaflet was revised in
July 2023

© Pfizer Australia Pty Ltd

® Registered Trademark

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Zavedos

Active ingredient

Idarubicin hydrochloride

Schedule

S4

 

1 Name of Medicine

Idarubicin hydrochloride.

2 Qualitative and Quantitative Composition

Each vial contains 5 mg/5 mL or 10 mg/10 mL of idarubicin hydrochloride.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.

Red-orange, clear, mobile solution, free from particles.

4 Clinical Particulars

4.1 Therapeutic Indications

Zavedos is indicated for use in acute myelogenous leukaemia (AML) in adults for remission induction in untreated patients or for remission induction in relapsed or refractory patients. Zavedos may be used in combination chemotherapy regimens involving other cytotoxic agents.

4.2 Dose and Method of Administration

Dose.

For induction therapy in adult patients with AML, the following dose schedules are recommended.
Zavedos 12 mg/m2 daily for three days by slow (10-15 min) intravenous injection in combination with cytarabine 100 mg/m2 daily given by continuous infusion for seven days. In patients with unequivocal evidence of leukaemia after the first induction course, a second course may be administered. Administration of the second course should be delayed in patients who experienced severe mucositis, until recovery from this toxicity has occurred, and a dose reduction of 25% is recommended.

Dosage adjustment.

Hepatic and renal impairment.

Zavedos should not be administered in patients with severe renal and liver impairment (see Section 4.3 Contraindications). Dose adjustment should be considered in patients with moderate liver and renal impairment (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use). With anthracyclines a 50% dose reduction is generally employed if bilirubin levels are in the range 20.4-51.0 micromole/L.
All dosage schedules should take into account the haematological status of the patient and all the doses of other cytotoxic drugs when used in combination.

Method of administration.

Intravenous infusion.
Zavedos solution for injection must be administrated only by the intravenous route and should be given via tubing of a freely running intravenous infusion of 0.9% sodium chloride injection, taking 10-15 minutes over the injection.
The tubing should be attached to a butterfly needle or other suitable device and inserted preferably into a large vein. This technique minimises the risk of thrombosis or perivenous extravasation, which can lead to severe cellulitis and necrosis. Venous sclerosis may result from injection into small veins or repeated injections in the same vein.
Care in the administration of Zavedos will reduce the chance of perivenous infiltration. It may also decrease the chance of local reactions such as urticaria and erythematous streaking.
During intravenous administration of Zavedos, extravasation may occur, with or without an accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein. If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs (½ hour immediately, then ½ hour 4 times per day for 3 days) be placed on the area of extravasation and that the affected extremity be elevated.
Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and plastic surgery consultations obtained early if there is any sign of local reaction such as pain, erythema, oedema or vesication. If ulceration begins or there is persistent pain at the site of extravasation, early wide excision of the involved area should be considered. Also see Section 4.4 Special Warnings and Precautions for Use, Effects at site of injection.

Instructions for use and handling and disposal.

Caution in handling and preparation of the solution must be exercised, as skin reactions associated with Zavedos may occur. Skin exposed accidentally to Zavedos should be washed thoroughly with water, soap and water or sodium bicarbonate solution and, if the eyes are involved, standard irrigation techniques should be used immediately. Medical attention should be sought. The following protective recommendations are given due to the toxic nature of the substance.
Personnel should be trained in good technique for handling Zavedos.
Pregnant staff should be excluded from working with Zavedos.
The use of goggles, disposable masks and gloves and protective gowns are recommended during preparation and administration of the drug.
A designated area should be defined (preferably under a laminar flow system). The work surface should be protected by disposable, plastic backed absorbent paper.
All items used for administration or cleaning, including gloves, should be placed in high-risk waste disposal bags for high temperature incineration.
Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as indicated previously.

4.3 Contraindications

Zavedos therapy is contraindicated in patients with severe renal and liver impairment or patients with uncontrolled infections. It should also not be administered to individuals with hypersensitivity to idarubicin or any other component of the product (see Section 6.1 List of Excipients) and/or other anthracyclines.
Zavedos therapy is contraindicated in patients with severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias, persistent myelosuppression, or previous treatment with maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones.
Zavedos therapy is contraindicated in pregnant women or women wishing to become pregnant (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

4.4 Special Warnings and Precautions for Use

General.

Zavedos is intended for use under the direction of those experienced in leukaemia chemotherapy. Close monitoring for toxicity is mandatory.
Facilities with laboratory and supportive resources adequate to monitor drug tolerability and protect and maintain a patient compromised by drug toxicity should be available. It must be possible to treat a severe haemorrhagic condition and/or severe infection rapidly and effectively.
The drug should not be given to patients with pre-existing bone marrow depression induced by previous drug therapy or radiotherapy unless the benefit warrants the risk.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia and generalised infections) before beginning treatment with idarubicin.
Pre-existing heart disease and previous therapy with anthracyclines, especially at high cumulative doses, or other potentially cardiotoxic agents are cofactors for increased risk of idarubicin induced cardiac toxicity; the benefit to risk ratio of idarubicin therapy in such patients should be weighed before starting treatment with Zavedos. Like most other cytotoxic agents, idarubicin has mutagenic properties and is carcinogenic in rats.

Haematologic toxicity.

Zavedos is a potent bone marrow suppressant. Myelosuppression, primarily of leucocytes, will therefore occur in all patients given a therapeutic dose of this agent and careful haematological monitoring including granulocytes, red cells and platelets is required.

Secondary leukaemia.

Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines, including idarubicin. Secondary leukaemia is more common when such drugs are given in combination with DNA damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukaemias can have a 1 to 3 year latency period.

Cardiac function.

Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (acute) or late (delayed) events.

Early (acute) events.

Early cardiotoxicity of idarubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities, such as nonspecific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity.

Late (delayed) events.

Delayed cardiotoxicity usually develops late in the course of therapy or within 2 to 3 months after completion of treatment, but later events, several months to years after completion of treatment have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of CHF such as dyspnoea, pulmonary oedema, dependent oedema, cardiomegaly and hepatomegaly, oliguria, ascites, pleural effusion and gallop rhythm. Subacute effects such as pericarditis/ myocarditis have also been reported. Life threatening CHF is the most severe form of anthracycline induced cardiomyopathy and represents the cumulative dose limiting toxicity of the drug.
Myocardial toxicity, as manifested by potentially fatal congestive heart failure, acute life threatening arrhythmias or other cardiomyopathies, may occur during therapy or several weeks after termination of therapy.
Idarubicin related cardiomyopathy was reported in 5% of patients who received cumulative intravenous doses of 150 to 290 mg/m2. Although cumulative dose limits are yet to be defined, available data on patients treated with Zavedos capsules indicate that total cumulative doses up to at least 400 mg/m2 have a low probability of cardiotoxicity. Should congestive heart failure (CHF) occur, treatment with digitalis, diuretics, sodium restriction and bed rest is indicated.
Cardiac function should be monitored carefully during treatment in order to minimise the risk of cardiac toxicity of the type described for other anthracycline compounds. Risk factors for cardiac toxicity include concomitant or previous radiation to the mediastinal/ pericardial area, previous treatment with other anthracyclines or anthracenediones at high cumulative doses, and concomitant use of drugs with the ability to suppress cardiac contractility or other potentially cardiotoxic agents (e.g. trastuzumab). Anthracyclines including idarubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab (variable half-life; washout period up to 7 months), may also be at an increased risk of developing cardiotoxicity.
Note: Trastuzumab emtansine has a shorter half-life of approximately 4 days. The half-life of trastuzumab is variable. Trastuzumab (Herceptin) may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
The benefit to risk ratio of Zavedos therapy in such patients should be weighed before starting treatment. The risk of such myocardial toxicity may also be higher in patients with a pre-existing heart disease or particular clinical situation due to their disease (anaemia, bone marrow depression, infections, leukaemic pericarditis and/or myocarditis).
While there is no reliable method for predicting acute congestive heart failure, cardiomyopathy induced by anthracyclines is usually associated with persistent QRS voltage reduction, increase beyond normal limits of the systolic time interval (PEP/LET) and decrease of the left ventricular ejection fraction (LVEF) from pretreatment baseline values.
Assessment of cardiac function (evaluation of LVEF) with an ECG and either a multiple gated acquisition (MUGA) scan or an echocardiogram (ECHO) should be performed prior to starting therapy with Zavedos. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up. Early clinical diagnosis of drug induced myocardial damage appears to be important for pharmacological treatment to be useful.

Gastrointestinal disorders.

Severe enterocolitis with perforation has been reported rarely. The risk of perforation may be increased by instrumental intervention. The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.

Use in hepatic impairment.

Since impairment of hepatic function may affect the disposition of idarubicin, liver function should be evaluated with conventional clinical laboratory tests (using serum bilirubin) prior to and during treatment. Idarubicin is contraindicated in severe hepatic impairment. Also see Section 4.2 Dose and Method of Administration.

Use in renal impairment.

Since impairment of renal function may affect the disposition of idarubicin, kidney function should be evaluated with conventional clinical laboratory tests (using serum creatinine as indicators) prior to and during treatment. Idarubicin is contraindicated in severe renal impairment. Also see Section 4.2 Dose and Method of Administration.

Tumour lysis syndrome.

Idarubicin may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies drug induced rapid lysis of neoplastic cells ('tumour lysis syndrome'). Blood uric acid levels, potassium, calcium, phosphate and creatinine should be evaluated after initial treatment. Hydration, urine alkalinisation and prophylaxis with allopurinol to prevent hyperuricaemia may minimise potential complications of tumour lysis syndrome. Appropriate measures must be taken to control any systemic infection before beginning therapy.

Effects at site of injection.

With intravenous administered Zavedos, extravasation at the site of injection can cause pain, severe local tissue lesions (vesication, severe cellulitis) and necrosis. Extravasation may occur, with or without accompanying stinging or burning sensation, even if blood returns well on aspiration of the infusion needle. If signs or symptoms of extravasation occur, the injection or infusion should be terminated immediately and restarted in another vein (see Section 4.2 Dose and Method of Administration).
Phlebosclerosis may result from an injection into a small vessel or from previous injections into the same vein.

Immunosuppressant effects/ increased susceptibility to infections.

Administration of live or live attenuated vaccines in patients immunocompromised by chemotherapeutic agents including idarubicin may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving idarubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

Embryo-fetal toxicity.

Idarubicin can cause genotoxicity. An effective method of contraception is required for both male and female patients during and for a period after treatment with idarubicin. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available (see Section 4.6 Fertility, Pregnancy and Lactation; Section 5.3 Preclinical Safety Data).

Other.

Thrombophlebitis and thromboembolic phenomena, including pulmonary embolism, have been coincidentally reported with the use of idarubicin. The risk of thrombophlebitis at the injection site may be minimised by following the recommended procedure for administration.

Use in the elderly.

No data available.

Paediatric use.

In infants and children there appears to be a greater susceptibility to anthracycline induced cardiac toxicity, and a long-term periodic evaluation of cardiac function has to be performed.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Zavedos is a potent myelosuppressant, and combination chemotherapy regimens which contain other agents having a similar action may be expected to lead to additive myelosuppressive effects, especially with regard to bone marrow/ haematologic and gastrointestinal effects (see Section 4.4 Special Warnings and Precautions for Use).
The use of idarubicin in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), requires monitoring of cardiac function throughout treatment (see Section 4.4 Special Warnings and Precautions for Use).
Changes in hepatic or renal function induced by concomitant therapies may affect idarubicin metabolism, pharmacokinetics and therapeutic efficacy and/or toxicity (see Section 4.4 Special Warnings and Precautions for Use).
An additive myelosuppressant effect may occur when radiotherapy is given concomitantly or within 2-3 weeks prior to treatment with idarubicin.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Idarubicin can induce chromosomal damage in human spermatozoa. For this reason, males undergoing treatment with idarubicin should use effective contraceptive methods. Both men and women should seek advice on fertility preservation before treatment.
(Category D)
Zavedos should not be used during pregnancy (see Section 4.3 Contraindications).
There is no information as to whether idarubicin adversely affects fertility or causes teratogenesis in humans. However, it is teratogenic and embryotoxic in rats at intravenous doses of 0.7-1.4 mg/m2/day. In rabbits, no evidence of teratogenicity was seen at the highest dose tested (2.2 mg/m2/day or one-fifth of the human intravenous dose), which caused some maternal deaths. If the patient becomes pregnant during therapy, the patient should be informed of the potential hazard to the fetus.

Women of childbearing potential/contraception in males and females.

Women of childbearing potential should be advised to avoid becoming pregnant during treatment. Women of childbearing potential should be advised to use effective contraception during treatment with idarubicin and for at least 6.5 months after the last dose. Men with female partners of childbearing potential should be advised to use effective contraception during treatment with idarubicin and for at least 3.5 months after the last dose.
 It is not known whether idarubicin or its metabolites are excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from idarubicin, advise lactating women not to breastfeed during treatment with idarubicin and for at least 14 days after last dose.

4.7 Effects on Ability to Drive and Use Machines

The effect of idarubicin on the ability to drive or use machinery has not been systematically evaluated. Special care should be taken if it is essential that patients drive or operate machinery while undergoing treatment with Zavedos, especially if in a debilitated condition.

4.8 Adverse Effects (Undesirable Effects)

Severe myelosuppression and cardiac toxicity are the two major adverse effects. Most side effects are dose dependent, e.g. bone marrow depression and cardiotoxicity. All side effects except cardiomyopathy are reversible.
Adverse reactions that occur more frequently than 1% include:

Infections and infestations.

Infection, sepsis/septicaemia.

Neoplasms benign, malignant and unspecified.

Secondary leukemias (acute myeloid leukaemia and myelodysplastic syndrome).

Immune system disorders.

Anaphylaxis.

Blood and lymphatic system disorders.

Anaemia, leucopenia, neutropenia, thrombocytopenia and bone marrow depression.

Gastrointestinal disorders.

Abdominal pain or burning sensation, acute nausea and vomiting, mucositis/stomatitis, oesophagitis, diarrhoea, burning sensation, erosions/ulceration, gastrointestinal tract bleeding, colitis (including severe enterocolitis/neutropenic enterocolitis with perforation).

Skin and subcutaneous tissue disorders.

Alopecia, skin rash/itch, acral erythema, alopecia, hypersensitivity of irradiated skin ('radiation recall reaction'), local toxicity, skin changes, skin and nail hyperpigmentation, urticaria.

Renal disorders.

Idarubicin may impart a red colour to the urine for 1-2 days after administration and patients should be advised that this is no cause for alarm.

Cardiac disorders.

Cardiomyopathy, sinus tachycardia, tachyarrhythmias, atrioventricular and bundle branch block, subacute effects such as pericarditis/myocarditis.

Vascular disorders.

Phlebitis, thrombophlebitis, thromboembolism, vasomotor instability (hot flushes), haemorrhage, shock.

Metabolism and nutrition disorders.

Anorexia, dehydration, hyperuricaemia.

General disorders and administration site conditions.

Fever, chills.

Investigations.

Asymptomatic reductions in left ventricular ejection fraction, ECG abnormalities, elevation of liver enzymes and bilirubin.

Description of selected adverse events.

Myelosuppression.

Haematological toxicity occurs in all patients receiving therapeutic doses of Zavedos and severe myelosuppression is the major toxicity associated with Zavedos therapy. Leucopenia is usually severe, with neutrophils as the white blood cell most significantly affected; thrombocytopenia and anaemia may also occur. During the period of myelosuppression, patients are at the risk of developing infection and bleeding which may be life-threatening or fatal.
Leucocyte and platelet nadirs are usually reached 10 to 14 days following administration of the drug, however cell counts generally return to normal levels during the third week.
Clinical consequences of bone marrow/ haematological toxicity may be fever, infections, sepsis/ septicaemia, septic shock, haemorrhages, tissue hypoxia or death. Intravenous antibiotics should be given in the presence of febrile neutropenia.

Gastrointestinal disorders.

Nausea and/or vomiting, mucositis (usually involving the oral mucosa and appearing 3-10 days after starting treatment), abdominal pain or burning sensation, diarrhoea and oesophagitis may occur but severe (WHO grade 4) gastrointestinal toxicity is reported in less than 5% of patients.
Severe vomiting and diarrhoea may cause dehydration. Nausea and vomiting may be prevented or alleviated by the administration of appropriate antiemetic therapy.
Severe enterocolitis (neutropenic enterocolitis) with perforation has been reported. The possibility of perforation should be considered in patients who develop severe abdominal pain and appropriate steps for diagnosis and management should be taken.

Skin and subcutaneous tissue disorders.

Alopecia is reported frequently and dermatological reactions including rash/ itch, urticaria and a bullous erythrodermatous rash of the palms and soles can occur. The dermatological reactions are usually attributable to concomitant antibiotic therapy, skin changes, skin and nail hyperpigmentation, hypersensitivity of irradiated skin ('radiation recall reaction'), acral erythema, local toxicity and local reactions including hives at the injection site have been reported.

Cardiac disorders.

As in the case of other anthracyclines, cardiac toxicity, as manifested by congestive heart failure (frequently attributed to fluid overload), serious life threatening arrhythmias including atrial fibrillation, chest pain, myocardial infarction and asymptomatic declines in LVEF have been reported in patients undergoing induction therapy for AML (see Section 4.4 Special Warnings and Precautions for Use). Myocardial insufficiency and arrhythmias are usually reversible and occur in the setting of sepsis, anaemia and aggressive intravenous fluid administration. The events were reported more frequently in patients over age 60 years and in those with pre-existing cardiac disease. Serious cardiac impairment may be prevented through regular surveillance during the course of treatment (see Section 4.4 Special Warnings and Precautions for Use). Subacute effects, such as pericarditis/ myocarditis, have also been reported.

Hepatic and renal disorders.

Changes in hepatic and renal function tests are severe (grade 4) in less than 5% of patients, are usually transient and occur in the setting of sepsis and while patients are receiving potentially hepatotoxic and nephrotoxic antibiotics and antifungal agents.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Very high doses of idarubicin may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression within one or two weeks. Delayed cardiac failure has been seen with the anthracyclines up to several months after an overdose.
Two cases of fatal overdosage in patients receiving therapy for AML have been reported. The doses were 135 mg/m2 over 3 days and 45 mg/m2 of idarubicin and 90 mg/m2 of daunorubicin over a 3 day period.
There is no known antidote to Zavedos. Treatment should aim to support the patient and should utilise such measures as blood transfusions, reverse barrier nursing, antibiotics and symptomatic treatment of mucositis. Patients should be observed carefully and if signs of cardiac failure arise, should be treated along conventional lines.
Disposition studies with idarubicin in patients with severe renal failure or in those undergoing dialysis have not been carried out. The profound multicompartment behaviour, extensive extravascular distribution and tissue binding, coupled with the low unbound fraction available in the plasma pool, make it unlikely that therapeutic efficacy or toxicity would be altered by conventional peritoneal haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Zavedos is a semi synthetic antineoplastic anthracycline for intravenous use.

Mechanism of action.

Idarubicin is a cytotoxic agent. It is a DNA intercalating agent which reacts with topoisomerase II and has an inhibitory effect on nucleic acid synthesis. The compound has a high lipophilicity which results in an increased rate of cellular uptake compared with doxorubicin and daunorubicin.

Pharmacodynamic effects.

Idarubicin has been shown to have a higher potency with respect to daunorubicin and to be an effective agent against murine leukaemia and lymphomas. Studies in vitro on human and murine anthracycline resistant cells have shown a lower degree of cross resistance for idarubicin compared with doxorubicin and daunorubicin. Cardiotoxicity studies in animals have indicated that idarubicin has a better therapeutic index than daunorubicin and doxorubicin. The main metabolite, idarubicinol, has shown antitumour activities in experimental models both in vitro and in vivo. In the rat, idarubicinol administered at the same doses as the parent drug is less cardiotoxic than idarubicin.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Intravenous.

After intravenous administration of idarubicin, there is triphasic disposition in plasma. Estimates of the plasma half-life for the parent compound range from 10 to 35 hours. Idarubicin is extensively metabolised to an active metabolite, idarubicinol, which has a plasma half-life ranging from 41 to 69 hours.
The plasma clearance is higher than the expected hepatic plasma flow, indicating extensive extrahepatic metabolism. Protein binding in plasma is 97% for idarubicin and 94% for idarubicinol. For both compounds, the binding is concentration independent.
Peak cellular idarubicin concentrations are reached a few minutes after injection. Idarubicin and idarubicinol concentrations in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations. Idarubicin elimination half-life in cells is about 15 hours and is similar to that in plasma. The elimination half-life for idarubicinol in cells is 72 hours.
Excretion takes place via the liver and kidneys, mainly in the form of idarubicinol. After intravenous administration of 13 mg/m2 14C-idarubicin, 33% of the dose was excreted in urine and 39% in faeces after 14 days. Idarubicin excreted unchanged in urine accounts for 2-7% of the dose, and idarubicinol, 9-13%. In a patient with percutaneous biliary drainage, 17% of the dose was eliminated through the bile (as idarubicin plus idarubicinol) over five days.

Special populations.

Renal impairment.

Only limited information is available regarding the effect of an impaired renal function on the pharmacokinetics of idarubicin. A significant correlation is reported between the plasma clearance of idarubicin after intravenous dosing and creatinine clearance. In a study comparing patients with creatinine clearance < 60 mL/min and those with normal creatinine clearance, idarubicin AUC was increased on average by 38% and idarubicinol AUC by 120% in the patients with reduced creatinine clearance; however, there was considerable variability.

Hepatic impairment.

There is also limited information on the effect of impaired liver function on the pharmacokinetics of idarubicin. In a study comparing patients with liver metastases and mild liver impairment and those with normal liver function, there were no significant differences in idarubicin and idarubicinol pharmacokinetic parameters. However, in a patient with severe liver impairment, elimination of idarubicin was significantly delayed, the plasma elimination half-life being 112 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Idarubicin was genotoxic in most of the in vitro or in vivo tests performed. Idarubicin was mutagenic in vitro in reverse mutation assays with Salmonella typhimurium and Saccharomyces cerevisiae D4. In forward mutation assays in vitro, idarubicin was mutagenic in Chinese hamster V79 cells but not in Schizosaccharomyces pombe P1, either in vitro or ex vivo. Idarubicin was clastogenic in human lymphocytes and induced unscheduled DNA synthesis in rat hepatocytes in vitro and was clastogenic in the mouse micronucleus test in vivo.

Carcinogenicity.

Long-term carcinogenicity studies have not been conducted with idarubicin, but like most other cytotoxic agents, idarubicin has mutagenic properties and is carcinogenic in rats. In male dogs, testicular atrophy with inhibition of spermatogenesis and sperm maturation was observed at threshold idarubicin doses 1.8 mg/m2 administered intravenously or 3 mg/m2 administered orally (3 days/week for 13 weeks). These effects were not readily reversible after an eight week recovery period.

6 Pharmaceutical Particulars

6.1 List of Excipients

Glycerol, hydrochloric acid for adjustment to pH 3.5, water for injections.

6.2 Incompatibilities

Zavedos is not to be mixed with heparin since this causes precipitation, not to be mixed with alkaline solutions, since this causes rapid degradation of Zavedos, and it is not recommended that it be mixed with other drugs.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C. Refrigerate. Do not freeze. Protect from light.

6.5 Nature and Contents of Container

Zavedos solution for injection is supplied in single use only, polypropylene and Type I glass vials.
Not all presentations may be marketed.

6.6 Special Precautions for Disposal

All items used for administration or cleaning, including gloves should be placed in high-risk, waste disposal bags for high temperature incineration.
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Idarubicin hydrochloride is an odourless red-orange powder, slightly soluble in water, with a melting point of 173°C - 174°C. The molecular formula is C26H27NO9.HCl and the molecular weight is 533.95.

Chemical structure.


Chemical name: (7S,9S)-9-acetyl- 7,8,9,10-tetrahydro- 6,7,9,11-tetrahydroxy- 7-O-(2,3,6-trideoxy-3-amino-α- L-lyxo-hexopyranosyl)- 5,12-naphthacenedione hydrochloride.

CAS number.

57852-57-0.

7 Medicine Schedule (Poisons Standard)

S4, Prescription Only Medicine.

Summary Table of Changes